Soft chewable dosage form

ABSTRACT

The invention relates to a soft chewable dosage form comprising a first active pharmaceutical ingredient encapsulated in a lipid material that is embedded in the soft chewable dosage form and wherein the soft chewable dosage form comprises at least a second active pharmaceutical ingredient as well as a method of treating a subject suffering from a disease or disorder in the gastro intestinal tract using the soft chewable dosage form.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. application 62/747,267 filedon Oct. 18, 2018, the complete disclosure of which is herebyincorporated herein by reference for all purposes.

FIELD OF INVENTION

The invention relates to a soft chewable dosage form comprising a firstactive pharmaceutical ingredient encapsulated in a lipid material/matrixthat is embedded in a soft chewable dosage form and wherein the softchewable dosage form comprises at least a second active pharmaceuticalingredient, as well as a method of treating a subject suffering from adisease or disorder in the gastro intestinal tract using such a softchewable dosage form.

BACKGROUND OF INVENTION

Histamine H2-receptor antagonists, for example cimetidine, ranitidine,nizetidine, roxatine and famotidine, reduce acid secretion by actingdirectly on the acid-secreting parietal cell located within the gastricgland of the stomach wall.

Although histamine H2-receptor antagonists are remarkably effective inthe treatment of many gastric disorders, in particular peptic andgastric ulcers, there exist certain patient groups which do not respondto treatment. In addition, the time lapse between dosing and onset ofaction limits the potential benefit of histamine H2-receptor antagonistsin the treatment of acute, self-limiting gastric disorders.

Histamine H2-receptor antagonists are of potential benefit in theself-medication of acute, self-limiting gastric disorders such ashyperacidity. However, their slow onset of action is unlikely to meetthe consumer requirement for rapid relief of symptoms.

Co-administration of histamine H2-receptor antagonists and otherpharmaceutically active materials, including antacids, has beeninvestigated. The rationale for co-administration with antacid is thatthe antacid brings about rapid relief from the symptoms of excessstomach acidity by neutralization whereas the histamine H2-receptorantagonist acts independently by inhibiting secretion of acid from theparietal cell.

Antacids used today are made from a variety of inorganic salts such ascalcium carbonate, sodium bicarbonate, magnesium salts and aluminumsalts. Magnesium hydroxide and aluminum hydroxide are the most potentmagnesium and aluminum salts and are often used in combination. Inaddition, aluminum oxide, magnesium oxide, magnesium carbonate, aluminumphosphate, magaldrate, magnesium trisilicate, and aluminum sucrosesulfate (sucralfate) are also employed.

However, co-administration of famotidine is often very difficult becausefamotidine is extremely sensitive to humidity and can immediately startto degrade in such conditions.

SUMMARY OF THE INVENTION

The invention relates to the development of new improved soft chewabledosage form comprising a first active pharmaceutical ingredientencapsulated in a lipid material/matrix that is embedded in a softchewable dosage form and wherein the soft chewable dosage form comprisesat least a second active pharmaceutical ingredient. One examplecomprises famotidine encapsulated in a lipid material and embedded in asoft chewable dosage form comprising at least one antacid.

The invention enables for the first time the delivery of afamotidine/antacid combination in a soft chewable dosage form. Theformat ensures the stability of famotidine and offers a better sensoryexperience in terms of soothing and coating the painful esophagealtissues, giving consumers a faster acting remedy.

Soft chew forms inherently have a high-water content. A high level ofwater can contribute to degradation (hydrolysis of famotidine) if rawfamotidine is blended into the matrix. In the case of the presentinvention, the lipid insert/material prevents ingress of water into thefamotidine particles and prevents further interaction and hydrolysis.

Finally, the invention relates to a method of using the soft chewabletablet as defined above and below in the application for the treatmentof a subject suffering from a disease or disorder in the gastrointestinal tract, such as heart burn.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows force measurements on samples with different amounts ofMCTs.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION Definitions

In the context of the present application and invention the followingdefinitions apply:

The term “soft chewable” is intended to mean a dosage form which retainsits integrity and texture upon chewing, does not break into discrete,solid pieces or particulates upon chewing and is intended to beswallowed. The soft chew is palatable, edible, and is similar in textureto confectionery taffy or nougat.

The term “% w/w” is intended to mean the percentage of aningredient(s)/the total percentage by weight of the composition (100%).

A “dosage”, “dosage form”, “dose unit” or “dose” as used herein meansthe amount of a pharmaceutical ingredient comprising therapeuticallyactive agent(s) administered at a time. “Dosage”, “dosage form”, “doseunit” or “dose” includes administration of one or more units ofpharmaceutical ingredient administered at the same time.

The term “gastric disease or disorder” is primarily intended to mean anincreased production of the acid secretion which leads to heartburn andbothersome gas symptoms in a subject, also named indigestion.Indigestion, also known as dyspepsia, is a condition of impaireddigestion. Symptoms may include upper abdominal fullness, heartburn,nausea, belching, or upper abdominal pain. People may also experiencefeeling full earlier than expected when eating. Dyspepsia is a commonproblem and is frequently caused by gastroesophageal reflux disease(GERD) or gastritis.

The Soft Chewable Dosage Form

In one embodiment the invention relates to a soft chewable dosage formcomprising a first active pharmaceutical ingredient encapsulated in alipid material/matrix that is embedded in a soft chewable dosage formand wherein the soft chewable dosage form comprises at least a secondactive pharmaceutical ingredient.

In one example the encapsulated active pharmaceutical ingredientcomprises at least one histamine H2-receptor antagonist, such ascimetidine, ranitidine, nizatidine, roxatidine and famotidine, theirpharmaceutically acceptable salts, isomers and salts of isomers.

In another embodiment the H2 receptor antagonist is famotidine and thesecond active pharmaceutical ingredient is at least one antacid.

The particle size of the lipid encapsulated famotidine is from about 100microns to about 5000 microns, such as from about 200 microns to about2000 microns.

The famotidine is embedded and present in the dosage form within a lipidmatrix as a solid bead. The bead may be applied on the surface orinserted (as an insert) into the soft chew dosage form. In order toprepare this bead, famotidine is suspended or dispersed in a lipid baseand deposited as a bead. It may be deposited and solidified as a beadwhich is later applied to the soft chew; or applied in a liquid form anddeposited on the soft chew which is solidified in-situ. Thissolidification may be facilitated by an additional cooling step at roomtemperature, or a temperature cooler that room temperature (25° C.). Thefamotidine is present in the lipid bead as a dispersed solid or in asolid solution.

The diameter of the lipid bead of the present invention is from about 2millimeters to about 15, or from about 3 millimeters to about 8millimeters. The weight of the lipid bead can range from about 20 mg toabout 150 mg, or from about 30 mg to about 80 mg.

In another embodiment, the famotidine is present as a plurality ofparticulates, wherein such particulates are coated with at least onelipid material or polymer. As used herein, a plurality of particulatesis defined of at least two particulate units comprising famotidine.

The at least one antacid is selected from the group consisting ofcalcium carbonate, sodium bicarbonate, magnesium hydroxide, aluminumoxide, aluminum hydroxide, magnesium oxide, magnesium carbonate,aluminum phosphate, magaldrate and magnesium trisilicate.

The lipid material that encapsulates/coats the active pharmaceuticalingredient is selected from the group consisting of Cetostearyl alcohol,Glyceryl dibehenate, glyceryl palmitostearate, mono/diglycerides orhydrogenated vegetable oil or vegetable oil. Other examples of lipidmaterials include, but are not limited to, fatty acid esters such assucrose fatty acid esters, mono, di, and triglycerides, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoylmacrogol-32 glycerides; phospholipids such as phospholipids includephosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, andphosphotidic acid; waxes such as carnauba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; andfats such as hydrogenated vegetable oils such as for example cocoabutter, hydrogenated palm kernel oil, hydrogenated cottonseed oil,hydrogenated sunflower oil, and hydrogenated soybean oil; and free fattyacids and their salts. These lipids are also suitable for use as theprimary lipid within the lipid bead or material.

In certain embodiments an emulsifier or a second lipid may be added tothe primary lipid in order to soften or modify the texture of the lipidbead or material. The second lipid may also act as a plasticizer.Emulsifiers include but are not limited to polyethylene sorbitanmonooleate (polysorbate 60 and 80), glycerides, glyceryl esters,glyceryl monolineoleate, and monolineoleate. Suitable second lipids foruse as a plasticizer include but are not limited to medium chaintriglycerides (MCTs). The emulsifier or second lipid (plasticizer) maybe present within the lipid bead or material at an amount from about 5percent to about 50 percent, or from about 5 percent to about 30 percentby weight of the lipid bead or material.

If famotidine is the active pharmaceutical ingredient it may be in theform of granulate, bead or compressed tablet.

In addition to famotidine and antacid(s) the soft chewable dosage formmay also comprise simethicone as an active pharmaceutical ingredient.Simethicone may be present in the soft chew base comprising antacid, orin the lipid bead or pellet comprising famotidine.

The soft chewable tablet may further comprise one or more ingredient(s)selected from the list consisting of fats, proteins, colorings, flavors,sweeteners, thickeners, emulsifiers, antioxidants, preservatives,lubricants, glidants, gelling agents and disintegrants.

Example of flavors are peppermint, spearmint, eucalyptus, licorice,vanilla, caramel, mixed berries, mixed fruits, black current, blueberry, cherry and lemon.

If needed one or more of the active pharmaceutical ingredients are tastemasked. Taste masking technologies are well known for a person skilledin the art.

Examples of excipients include fats, proteins, fillers, glidants,lubricants, sweeteners, flavors, coloring agents, fillers,binding/gelling agents and mixtures thereof.

Suitable lubricants include long chain fatty acids and their salts, suchas magnesium stearate and stearic acid, talc, glycerides waxes, andmixtures thereof.

Suitable glidants include colloidal silicon dioxide.

Examples of sweeteners include, synthetic or natural sugars; artificialsweeteners such as saccharin, sodium saccharin, sucralose, aspartame,acesulfame, thaumatin, glycyrrhizin, sucralose, cyclamate,dihydrochalcone, alitame, miraculin and monellin; sugar alcohols such assorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; sugarsextracted from sugar cane and sugar beet (sucrose), dextrose (alsocalled glucose), fructose (also called laevulose), and lactose (alsocalled milk sugar); isomalt, stevia, and mixtures thereof.

Examples of coloring agents include lakes and dyes approved as a foodadditive.

Examples of fillers that may be used include corn syrup, sucrose,starches, fats, proteins and gelatin. Additional materials that may beused in the soft chew base include corn syrup solids, sucrose, starches,fats, proteins and/or gelatin.

In one embodiment the dosage form is coated. The dosage form may becoated with a sugar or sugar alcohol-based coating or a film coating.Examples of materials for sugar or sugar alcohol-based coatings includebut are not limited to sucrose, dextrose or xylitol. Examples ofpolymers for use in a film coating include but are not limited tohypromellose and polyvinyl alcohol and polyvinyl alcohol:polyethyleneglycol co-polymers and mixtures thereof.

The amount of famotidine may be from about 2 to about 30 mg and theamount of the antacid(s) from about 200 to about 3000 mg. The amount offamotidine within the lipid bead portion may be from about 5 percent toabout 40 percent, or from about 10 percent to about 30 percent by weightof the lipid bead portion.

The histamine H2-receptor antagonist such as famotidine may be presentin an amount of from about 2 mg to about 30 mg, such as 4 mg to 20 mg or8 mg to 12 mg or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mg.

The antacid may be present in an amount of from about 200 to about 3000mg. If two different antacids are utilized, they may be in the sameamount or different amounts depending on the specific combinations.Examples are a dosage form having calcium carbonate in an amount fromabout 400 to about 1000 mg, such as 600, 700, 800, 900 or 1000 mg andmagnesium hydroxide in an amount from about 50 to about 300 mg, such asabout 100-about 200 mg, such as 100, 110, 120, 130, 140, 150, 160, 165,170, 180, 190 or 200 mg. If aluminum oxide or aluminum hydroxide is usedit may be used in an amount from about 200 to about 600 mg, such as 300,400, 500 or 600 mg.

In another aspect the invention relates to a soft chewable tablet,wherein the encapsulated active pharmaceutical ingredient is loperamideand the other active pharmaceutical ingredient is at least onesimethicone.

It is also desirable for the lipid bead containing famotidine and thesurrounding soft chew base containing antacid to have a similar textureupon chewing. The texture can be determined through analysis of forceover time. In this aspect of the invention, the force-over-time totalarea difference is less than 10000 g/sec between the lipid bead and thesoft chew base.

In another aspect of the invention the famotidine does not degrade overtime. In this aspect the amount of total famotidine impurities in thedosage form is less than 1.5% when stored at 40° C. and 75% relativehumidity for 3 months, and less than 1.0% for any single impurity whenstored at 40° C. and 75% relative humidity for 3 months.

The following examples are intended to illustrate, but not to limit, theinvention in any manner, shape, or form, either explicitly orimplicitly.

Example 1: Preparation of Famotidine Bead (Insert) in Meltable EdibleMatrix

The famotidine hot melt solution and integrated soft chew were preparedas follows:

-   -   1. Approximately 30 g batches were prepared according to the        base ratio formula in Table 1.    -   2. Materials in the meltable edible matrix were melted in a        stainless-steel vessel at approximately 70° C. Famotidine was        dispersed in the molten material and was continuously mixed to        maintain uniform distribution.    -   3. A pipette was used to transport measured amount of molten        mixture to form beads which then solidified upon cooling.    -   4. Variations in separate materials within the Base formula are        shown in Table 2

TABLE 1 Base Famotidine Bead Edible Matrix Formula Ingredient mg/Bead %W/W Meltable Edible Matrix* 56.7 85.00 Famotidine (Fine Powder) 10.015.00 TOTAL 66.7 100.00 *Lipophilic thermoplastic material which in someexamples also contains a plasticizer to soften the material.

TABLE 2 Initial Ingredients for Famotidine Containing Beads Ingredientmg/Tab % W/W FORMULA 1 SP Crodacol CS50¹ (Cetostearyl alcohol) 56.6785.00 Famotidine 10.00 15.00 66.67 100.00 FORMULA 2 Compritol 888 ATO²(Glyceryl dibehenate) 56.67 85.00 Famotidine 10.00 15.00 66.67 100.00FORMULA 3 Geleol³ (mono/diglycerides, NF) 56.67 85.00 Famotidine 10.0015.00 66.67 100.00 FORMULA 4 Sterotex (Hydrogenated cottonseed oil, NF)56.67 85.00 Famotidine 10.00 15.00 66.67 100.00 FORMULA 5 SP CrodacolCS50¹(Cetostearyl alcohol) 43.34 65.00 Gelucire⁴ 50/13 (Stearoylpolyoxyl-32 Glycerides) 13.33 20.00 Famotidine 10.00 15.00 66.67 100.00FORMULA 6 Compritol 888 ATO (Glyceryl dibehenate) 43.34 65.00 Gelucire50/13 (Stearoyl polyoxyl-32 Glycerides) 13.33 20.00 Famotidine 10.0015.00 66.67 100.00 ¹Commercially available from the Croda Corporation²Commercially available from the Gattefosse Corporation ³Commerciallyavailable from the Gattefosse Corporation ⁴Commercially available fromthe Gattefosse Corporation

Example 2: Stability Evaluation

The beads from Example 1 (Formulas 1-6) were exposed to differentconditions in amber glass jars to determine the stability of Famotidine.The famotidine and famotidine impurity assay was analyzed versus a stockstandard famotidine solution prepared at 400 μg/mL, using an HPLC withthe following parameters:

Column: Advanced Chromatography Technologies (ACE) C8, 3 μm (150 mm×4.6mm I.D.), ACE-112-1546

Mobile Phase: Gradient method of Sodium Phosphate Buffer:ACN (98:2v/v to30:70 over 26 minutes)

Flow rate: 1.0 mL/min

Injection volume: 15 mL

UV Detector at 278 nm

Sample preparation included the following steps:

For samples containing glyceryldibehenate (Compritol): 50 mL chloroformwas added and swirled until dissolved. Diluted to volume, withchloroform and mixed well.

For samples containing cetostearyl alcohol (Crodacol): 50 mL methanolwas added and mixed using mechanical shaker until dissolved. Diluted tovolume, with methanol and mixed well.

PART A: Storage in Amber Glass Jars:

Table 3 summarizes the stability study results.

TABLE 3 Stability Study Results-Beads Stored in Amber Glass Jars SampleCondition Assay FAM-A1^(a) FAM-A3^(b) FAM-A6^(c) FAM-UDP^(d)FAM-UDP2^(d) Formula 1 2 Weeks, RT 104.3 Not detected 0.125 Not detected0.145 Not detected Formula 2 2 Weeks, RT 101.9 Not detected 0.124 Notdetected 0.141 Not detected Formula 3 2 Weeks, RT 104.3 Not detected0.123 Not detected 0.149 Not detected Formula 4 2 Weeks, RT 103.8 Notdetected 0.119 0.144 0.136 Not detected Formula 5 2 Weeks, RT Notdetected Formula 6 2 Weeks, RT Not detected Formula 1 2 Weeks, 103.2 Notdetected 0.122 Not detected 0.140 Not detected 40° C/75% RH Formula 2 2Weeks, 100.6 Not detected 0.124 Not detected 0.158 Not detected 40°C/75% RH Formula 3 2 Weeks, 102.6 Not detected 0.123 0.17 0.169 Notdetected 40° C/75% RH Formula 4 2 Weeks, 103.4 Not detected 0.123 Notdetected 0.141 Not detected 40° C/75% RH Formula 5 2 Weeks, Not detected40° C/75% RH Formula 6 2 Weeks, Not detected 40° C/75% RH Formula 1 3Months, 130.3 Not detected 0.158 0.1 0.128 Not detected RT Formula 2 3Months, 121.2 Not detected 0.142 0.127 0.122 Not detected RT Formula 3 3Months, 120.3 Not detected 0.139 0.125 0.125 Not detected RT Formula 4 3Months, 123.4 Not detected 0.145 0.122 0.124 Not detected RT Formula 5 3Months, 100.0 Not detected 0.115 0.096 Not detected RT Formula 6 3Months, 94.8 0.102 0.110 0.107 0.118 Not detected RT Formula 1 3 Months,123.4 Not detected 0.151 0.095 0.121 Not detected 40° C/75% RH Formula 23 Months, 126.5 Not detected 0.161 0.107 0.219 Not detected 40° C/75% RHFormula 3 3 Months, 112.1 Not detected 0.152 0.107 0.605 0.731 40° C/75%RH Formula 4 3 Months, 124.9 Not detected 0.156 0.131 0.125 Not detected40° C/75% RH Formula 5 3 Months, 94.8 Not detected 0.112 Not detected0.091 Not detected 40° C/75% RH Formula 6 3 Months, 99.0 Not detected0.118 Not detected 0.277 Not detected 40° C/75% RH ^(a)FAM-A1:Famotidine Impurity A1 ^(b)FAM-A3: Famotidine Impurity A3 ^(c)FAM-A6:Famotidine Impurity A6 ^(d)FAM UDP: Famotidine Unspecified DegradationProduct RT - Room Temperature RH - Relative Humidity

Part B: Open Dish Storage

The formulas in SAMPLES 1 and 2 were selected for Open Dish Stabilityevaluation. The samples were placed into an open dish and placed intothe respective stability environment.

Table 4 summarizes the stability results of Famotidine in the beadsduring an Open Dish Study at 40° C./75% RH (relative humidity) for 3months. Minimum degradation of Famotidine was observed after 3 months.

TABLE 4 Stability Study Results-Open Dish Stability Sample ConditionAssay FAM-A1 FAM-A3 FAM-A6 FAM-UDP FAM-UDP2 Formula 1 Initial 100.4 Not0.119 Not 0.107 Not detected detected detected Formula 2 Initial 126.1Not 0.148 Not 0.135 Not detected detected detected Formula 1 2 Weeks, 98.6 Not 0.117 Not 0.094 Not 40° C./75% RH detected detected detectedFormula 2 2 Weeks, 120.0 Not 0.146 Not 0.126 Not 40° C./75% RH detecteddetected detected Formula 1 4 Weeks, 100.2 Not 0.133 Not 0.112 Not 40°C./75% RH detected detected detected Formula 2 4 Weeks, 115.8 Not 0.151Not 0.133 Not 40° C./75% RH detected detected detected Formula 1 3Months, 101.7 Not 0.157 Not Not 0.12 40° C./75% RH detected detecteddetected Formula 2 3 Months, 123.4 0.102 0.181 Not Not 0.15 40° C./75%RH detected detected

Example 3: Samples with Various Levels of Medium Chain Triglycerides(MCTs) & Force Measurement

In order to soften the beads so that the texture is similar to the softchew, different levels of MCT were added to Crodacol and Compritol asshown in Table 5, with associated force measurements.

Force Measurements were analyzed to compare the beads in Table 5 to thecommercial Rolaids® Soft Chew, to more closely match the organoleptictexture between a soft chew ingredient and the bead. Hardness wasmeasured using a Texture Profile Analyzer with the following testparameters:

Material Thickness—Solid block approx. 20 mm

Probe—Replaceable needle probe

Load cell—5 Kg

Test Profile—2 mm penetration @ 0.2 mm/sec

Results: Blends containing 30% MCT oil had the lowest hardness values(not included in graph). For stability studies, 15% MCT oil was selectedto minimize leaching of the oil from the bead into the soft chew matrix.

TABLE 5 Samples with Various levels of MCTs Force measurement Allcontain 15% Famotidine Formula Area F-T 1:2 (g · sec) Crodacol withoutMCT Formula 7 24,217.775 Compritol without MCT Formula 8 16,318.691Crodacol 15% MCT Formula 9 13,159.655 Compritol 15% MCT Formula 108,805.754 Crodacol 20% MCT Formula 11 9,599.951 Compritol 20% MCTFormula 12 7,040.707 Crodacol 30% MCT Formula 13 8713.572 Compritol 30%MCT Formula 14 4254.296 Soft Chew **Rolaids ® Chew Commercial 2** 6312A858.712

FIG. 1 shows the force measurements on samples with different amounts ofMCTs,

Example 4: Stability of Famotidine Beads in a Soft Chew

The Rolaids® softchew was used for a base stability study when combinedwith the famotidine beads. The stability results are shown in Table 7.

The bead ingredients for use in combination with the Softchew are shownin Table 6.

TABLE 6 Ingredients combined with Softchew Ingredient mg/Tab % W/WFORMULA 15 Compritol 888 ATO (Glyceryl dibehenate) 46.7 70.00 LabrafacLipophile WL 1349 (MCT oil)* 10.0 15.00 Famotidine 10.0 15.00 66.7100.00 FORMULA 16 SP Crodacol CS50 (Cetostearyl alcohol) 46.7 70.00Labrafac Lipophile WL 1349 (MCT oil)* 10.0 15.00 Famotidine 10.0 15.0066.7 100.00 *MCT Oil was added to soften the bead matrix

Sample Prep for Stability Study: 5 gm Rolaids® Softchew was cut into 6pieces. Approximately total of 200 mg of beads with Famotidine wereweighed out for each test condition. One or two beads were inserted intoeach cut chew piece, and was performed twice for each condition.

Sample Storage: Samples were placed in an amber jar and placed onstability at initial and 40 C/75% RH for 2 weeks, 4 weeks, 2 months and3 months timepoints.

The following ingredients are displayed on the package for thecommercial Rolaids® Softchew.

Active Ingredients

In Each Chew: Calcium Carbonate USP (1330 mg), Magnesium Hydroxide USP(235 mg).

Inactive Ingredients

Corn Starch, Corn Syrup, Corn Syrup Solids, Glycerin, HydrogenatedCoconut Oil, Lecithin, Natural and Artificial Flavors, Red 40 Lake,Sucrose, Water.

Other Information

Each chew contains: calcium 535 mg, magnesium 100 mg. Store between 68degrees to 77 degrees F. (20 degrees to 25 degrees C.) in a dry place.

TABLE 7 Stability Results for Famotidine Bead combined with Soft ChewSample Condition Assay FAM-A1^(a) FAM-A3^(b) FAM-A6^(c) FAM-UDP FAM-UDP2Formula 15 + Soft Chew Sample 1 Initial 122.0 0.062 0.148 Not 0.161 Notdetected detected Sample 2 Initial 122.1 0.063 0.148 Not 0.157 Notdetected detected Sample 3 2 Weeks, 121.6 0.095 0.154 Not Not 0.150 40°C./75% RH detected detected Sample 4 2 Weeks, 125.8 0.101 0.160 0.045Not 0.156 40° C/75% RH detected Sample 5 4 Weeks, 123.5 0.097 0.160 NotNot 0.145 40° C/75% RH detected detected Sample 6 4 Weeks, 121.0 0.0940.155 Not Not 0.149 40° C/75% RH detected detected Sample 7 2 Months,114.8 0.086 0.143 0.054 Not 0.128 40° C/75% RH detected Sample 8 2Months, 116.2 0.086 0.144 0.053 Not 0.131 40° C/75% RH detected Sample 92 Months, 98.4 0.073 0.122 0.062 Not 0.111 40° C/75% RH detected Sample10 2 Months, 94.3 0.067 0.115 0.052 Not 0.107 40° C/75% RH detectedSample 11 3 Months, 123.0 0.065 0.146 Not Not 0.118 40° C/75% RHdetected detected Sample 12 3 Months, 121.5 0.074 0.144 0.039 Not 0.11940° C/75% RH detected Sample 13 3 Months, 98.0 Not 0.111 Not Not 0.08840° C/75% RH detected detected detected Sample 14 3 Months, 97.1 0.0440.108 0.043 Not 0.091 40° C/75% RH detected Formula 16 + Soft ChewSample 1 Initial 99.1 0.048 0.121 Not 0.129 Not detected detected Sample2 Initial 99.8 0.05 0.122 Not 0.129 Not detected detected Sample 3 2Weeks, 88.4 0.044 0.110 Not Not 0.188 40° C/75% RH detected detectedSample 4 2 Weeks, 95.9 0.074 0.122 0.060 Not 0.393 40° C/75% RH detectedSample 5 4 Weeks, 86.3 0.064 0.112 Not Not 0.280 40° C/75% RH detecteddetected Sample 6 4 Weeks, 92.6 0.070 0.120 0.054 Not 0.317 40° C/75% RHdetected Sample 7 2 Months, 74.7 Not 0.091 Not Not 0.095 40° C/75% RHdetected detected detected Sample 8 2 Months, 72.0 Not 0.087 Not Not0.091 40° C/75% RH detected detected detected Sample 9 3 Months, 63.0Not 0.072 Not Not 0.057 40° C/75% RH detected detected detected Sample10 3 Months, 63.5 Not 0.073 Not Not 0.059 40° C/75% RH detected detecteddetected

Example 5: Coated Particulates and Dosage Form

Part A: Famotidine Granulation

TABLE 8 Granulation ingredients for Famotidine Particles (1.5 kg batch)% (w/w) Grams for 1.5 kg batch Lactose Monohydrate, Impalpable NF 81.001215 Famotidine USP 13.00 195 Hypromellulose E5 Premium USP 6.00 90Purified Water USP xxx 810

-   -   1. Lactose Monohydrate & Famotidine were passed through a 40        mesh screen.    -   2. Two-thirds of total water was heated to 70-80° C. The        Hypromellose was slowly added to water while mixing using a high        shear mixer. The remaining water was added. The solution was        cooled and allowed to de-aerate.    -   3. Granulation was carried out in a Huttlin Diskj et unit by        spraying the granulating fluid from Step 2 at 50 cc/min. After        granulation was completed, the particles were dried and        discharged for hot melt coating.    -   4. After granulation, pass material through 18 mesh before hot        melt coating.

Part B: Hot Melt Coating

-   -   For hot melt coating, Glyceryl palmitostearate (commercially        available as Precirol ATO from the Gattefosse corporation) is        heated to a temperature of about 60° C. and sprayed on        Famotidine granulation from Part A, in the Huttlin Diskj et        unit. The particles were coated with 30% weight gain.

Part C: Soft Chew Formulation Incorporating Coated Particulates

The following dosage form was prepared using the famotidine coatedparticles in Part A.

TABLE 9 With Famotidine mg/5 g (g/batch) % piece Dextrose Equivalent 42Corn Syrup- 126 31.5 1575 Cooked (85% solids) Calcium Carbonate 64 16800 Mag Hydroxide 13.2 3.3 165 Coated Famotidine 12.4 3.1 155Confectionary 10X Sugar 116 29 1450 Corn Syrup Solids 32 8 400 Sucralose2.8 0.7 35 Glycerin 6 1.5 75 Coconut Oil 24 6 300 Lecithin 2.4 0.6 30Flavors 1.2 0.3 15 Total 400 100 5000 Note: Coated Famotidine is at 6.5%potency

-   -   1. Blending process: The 42 Corn syrup was heated to 90° C. and        blended with the glycerin using a laboratory overhead mixer.    -   2. The Confectionery sugar, calcium carbonate, magnesium        hydroxide, corn syrup solids were added to the liquid blend in        Step 1.    -   3. In a separate container Coconut oil was heated to 40-45° C.        and blended with Lecithin.    -   4. The coated famotidine particles from Part A were blended with        Coconut oil and Lecithin mixture and then added to the blend        from Step 2. The flavor and color were added at the end. The        temperature of the final mixture was approximately 40° C. during        the addition of coated famotidine.    -   5. The soft chew blend was mixed until uniform.    -   6. The blend was cooled and solidified and manually cut into 5 g        pieces.

1.-16. (canceled)
 17. A method for treating a subject suffering from adisease or disorder in the gastro intestinal tract comprisingadministering a soft chewable dosage form comprising a first activepharmaceutical ingredient encapsulated in a lipid material/matrix,wherein the lipid encapsulated active pharmaceutical ingredient isembedded in the soft chewable dosage form, and wherein the soft chewabledosage form comprises at least a second active pharmaceuticalingredient.
 18. (canceled)